The goal of this exploratory proposal is to address the question of whether C. elegans can be used to provide insights into the understanding of the mechanisms by which bacterial virulence factors regulate host gene expression to inhibit innate immunity at the whole animal level. Many bacterial pathogens, including potential agents of biological warfare, share strategies to infect and colonize a wide range of animals. This suggests an ancient origin for the interactions between virulence factors and their targets in the host, and opens the possibility of using alternative non-vertebrate models to accelerate the identification and characterization of both pathogen and host signaling pathways that can be targeted for intervention. We have been using a genetic approach to study the interaction between bacterial virulence factors and their targets in the model genetic organism Caenorhabditis elegans. Using forward and reverse genetic approaches, we have identified a variety of Salmonella virulence-related genes required for pathogenesis in C. elegans and mammals, including genes related to the Salmonella type III secretion system (TTSS) dedicated to export effector proteins that facilitate bacterial pathogenesis by specifically interfering with host cellular processes. We have shown that when expressed in the C. elegans intestinal cells, effector protein SptP makes the animals more susceptible to S. enterica by targeting a p38 MARK signaling pathway that is also important for innate immunity in mammals. The Specific Aims of this proposal are: 1) Use microarrays to carry out transcriptional profiling analysis to identify specific innate immunity genes that are regulated by the intestinal expression of S. enterica virulence factors. 2) Use C. elegans RNAi libraries to identify genes which when inactivated enhance or suppress the increased susceptibility to S. enterica phenotype imposed by the expression of virulence factors in C. elegans. 3) Elucidate the mechanism by which the genes identified in Aims 1 and 2 contribute to C. elegans innate immunity pathways conserved in mammals.